Cancer remains a leading cause of mortality. In particular, breast cancer has become the most common cancer in women in the United States with 192,570 new cases anticipated in 2009, and it is the second leading cause of cancer death in American women, with 40,470 deaths expected this year (American, Cancer Society. (2009) Cancer Facts & Figures 2009 American Cancer Society). Despite the decades of advances in breast cancer therapies, the mortality rate due to breast cancer has been only slightly reduced in the United States. Over two third of patients initially diagnosed with early stage localized breast cancer eventually develop distant, late-stage disease (Bonadonna, et al. (1995) N Engl J Med 332: 901-906). The 5-year survival rate is still very poor, with about 26% for women with distant metastatic disease and 44% for women with recurrent disease (Giordano, et al. (2004) Cancer 100: 44-52).
Chemotherapy is considered the standard of care for many cancers, including breast cancer. Chemotherapy often decreases tumor size, allowing for subsequent surgery followed by radiation and further adjuvant chemotherapy. However, given that most current anticancer agents do not greatly differentiate between cancerous and normal cells, systemic toxicity and adverse effects (Hassett, et al. (2006) J Natl Cancer Inst 98: 1108-1117) associated with these chemotherapeutics limit their treatment efficacy. In addition, acquired drug resistance further decreases the treatment efficacy of the chemotherapy.
The response rate of breast cancer to first line chemotherapies is encouraging but the majority of patients have tumor progress in 7-10 months. Response to subsequent chemotherapies with various agents drops to 20-30% resulting from formidable cancer chemoresistance (Bernard-Marty, et al. (2004) Oncologist 9, 617-32). A number of mechanisms have been suggested to explain cancer chemoresistance or poor response to chemotherapy. The best studied mechanism of resistance is mediated through the alteration in the drug export pumps responsible for the removal of the therapeutic drugs (Trompier, et al. (2004) Cancer Res 6, 4950-6) Verapamil and its derivative trigger apoptosis through glutathione extrusion by multidrug resistance protein MRP1. One possible way to overcome this drug export pump is to give higher doses of chemotherapy. Although patients treated with high dose chemotherapy had significantly less breast cancer related events, the overall survival rate was not improved because of the treatment toxicity (Farquhar, et al. (2007) Cancer Treatment Reviews 33, 325-337; Farquhar, et al. (2005) Cochrane Database Syst Rev CD003139).
Liposome as a drug delivery carrier has been studied intensively in past several decades, due to its ability to modify the biodistribution of therapeutic agents. Liposomes are closed, self-assembled bilayer membranes, and are non-toxic, non-hemolytic, non-immunogenic, biocompatible/biodegradable, even upon repeated injections (Lian, et al. (2001) J Pharm Sci 90: 667-680; Moghimi, et al. (2001) Pharmacol Rev 53: 283-318). FDA approved liposomes, for example DOXIL which is a formulation of doxorubicin (Northfelt, et al. (1998) J. Clinical Oncology 16, 2445-2451; Ranson, et al. (1997) J Clin Oncol 15, 3185-3191; Gordon, et al. J(2001) Clin Oncol 19, 3312-3322; Al-Batran, et al. (2006) British Journal of Cancer 94, 1615-1620, Chia, et al. (2006) J Clin Oncol. 24, 2773-2778; Jones, et al. (2004) The Lancet Oncology 5, 575-577), can effectively control the pharmacokinetics and biodistribution of the drug, and specific tissues can be avoided or targeted. Thus, therapeutic index enhancement can be achieved both via toxicity reduction and efficacy enhancement (Maeda, et al. (2003) Int Immunopharmacol 3, 319-28.
Drug can be loaded either into the internal, trapped aqueous space, or in the lipid membranes. The grafting of hydrophilic, flexible chains of poly(ethylene glycol) (PEG) on the liposome surface (called “stealth” liposomes) has been shown to prolong their circulation lifetime (10-50 hours versus ˜minutes for non-pegylated liposomes alone) (Lasic, et al. (1999) Curr Opin Mol Ther 1: 177-185; Lasic, (1996) Nature 380: 561-562).
With the increase of the circulation time of liposomes, more liposomes are passively accumulated in the tumor tissue by enhanced permeability and retention effect (“EPR effect”), due to the leaky and defective architecture of the tumor vasculature. After accumulation in the tumor tissue, these long circulation liposomes remain in the interstitial space, and eventually release the encapsulated drug in the interstitial space by decomposition, or degradation. Therefore, liposomes are capable of delivery of a high dose of chemotherapy to patients with less systemic exposure. However, liposome releases drug into the interstitial space, and the transportation of the released drug into the tumor cells is a slow process, which allows the drug efflux pumps to effectively remove the drug from the cells, thereby reducing effectiveness.
Targeted liposomes are long circulating liposomes with targeting ligands conjugated to their surface to increase ligand binding efficacy. Immunoliposomes are targeted liposomes wherein the targeting moiety is an antibody, or antibody fragment having antigen-binding ability. Accumulation of the immunoliposomes in tumor tissue is also based on the EPR effect. Different from long circulating liposomes, after accumulation in the tumor tissue, immunoliposomes quickly bind to and internalize in the tumor cell via ligand-receptor interaction, and release the encapsulated drug in the tumor cell. See Mamot et al., Cancer Res 2005; 65:11631-11638. High dose encapsulated drug delivered directly into the tumor cells by the ligand-receptor interaction enhances the ability to overcome cancer drug resistance.
The human epidermal growth factor receptor-2 (Her-2/neu) is found to be overexpressed in ˜25%-30% of breast cancer cells. Thus, anti-Her-2/neu immunoliposome has been proposed as a promising delivery system to achieve targeted drug delivery for the treatment of Her-2/neu overexpressing breast cancer. See. e.g., Park et al., Clin Cancer Res. 2002 (4):1172-81.
Targeted delivery of a therapeutic drug to a diseased site can potentially decrease the systemic exposure of chemotherapeutics without sacrificing the therapeutic efficacy. However, single targeting delivery therapy has its limitation on therapeutic efficacy because there is no targeting moiety that can differentiate all the cancer cells from normal cells. For example only ˜25%-30% breast cancer cells overexpress Her-2/neu receptor.
Despite these advances in drug delivery, the heterogeneity of cancer, and breast cancer in particular, restricts the efficacy of treatment. Therefore, there is a critical need to develop more efficacious therapies or delivery methods that decrease systemic toxicity and side effects, and overcome the drug resistance in the cancer patient.
There remains a need for a treatment that can deliver a high dose of chemotherapy to patients with less systemic toxicity.